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The data from the 3 largest completed trials of homocysteine lowering with folic acid and vitamin B12with or without vitamin B6(VISP [Vitamin Intervention for Stroke Prevention] [1], NORVIT [Norwegian Vitamin Trial] [2], and HOPE-2 [Heart Outcomes Prevention Evaluation] [3]) consistently demonstrate no treatment benefit in patients with established vascular disease. These trials primarily evaluated white, middle-aged patients exposed to folate-fortified food (70% in HOPE-2, 100% in VISP) with only mild increases in homocysteine levels (<15 μmol/l). We agree that homocysteine-lowering therapy might potentially still prove to be beneficial in populations other than those studied—for example, in Southeast Asian patients where homocysteine levels typically exceed 15 μmol/l related to genetic or dietary factors, as suggested by Dr. Akhtar. However, subgroup analyses of the NORVIT and HOPE-2 trials provide useful insights. In 40% of patients in the NORVIT trial with a baseline homocysteine level above 13 μmol/l (mean homocysteine level was 17.4 μmol/l in this subgroup), homocysteine-lowering therapy provided no benefit. Similarly, no treatment benefit was observed among patients in the upper fifth of the baseline homocysteine distribution (≥19.7 μmol/l) in HOPE-2. It is quite possible that this lack of benefit may be related to inadequate statistical power in these subgroups. Thus, whether homocysteine-lowering therapy is going to be beneficial cannot be answered definitively until prospective, randomized trials are conducted in these populations. Ongoing large trials that are currently exploring these issues and the planned meta-analyses of all trials (12 trials involving about 52,000 participants with adequate statistical power, 7 in populations without fortification, and 5 in populations with fortification) (4) might help answer remaining relevant clinical questions.

With regards to folate therapy and in-stent restenosis, we do mention in our article (5) (p. 916) that slight, but not significant, benefits were observed in patients with elevated homocysteine levels (27.2% vs. 31.7%; p = NS).

A causal link between recent trends toward a lower rate of death from stroke in the U.S. and Canada and the fortification of food with folic acid remains speculative, as many other factors may have contributed to the decline (6).

Finally, we agree with Dr. Akhtar that a major obstacle to developing tools that address health problems of people in developing countries is the so-called 10/90 problem, whereby 90% of health research expenditure is targeted at problems affecting only 10% of the world’s population. Investment in health, both at the individual country level and at a global level, should therefore be encouraged to provide the necessary resources to develop these tools and enhance public health.

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